Role of IL-4 in persistent IgE formation.

Antigen-specific immunoglobulin E (IgE) responses against T-cell-dependent antigens, like allergens, can only be generated by cognate interaction between B-cells and T-helper (Th2) cells. This interaction is a prerequisite, donating the two signals that are essential for IgE production: CD40 ligation with its ligand gp39 and exposure to interleukin (IL)-4. Cytokine-mediated immunotherapy geared at intervention in allergic diseases, therefore aims at inhibiting the production or action of IL-4. In our view, based on two findings, this approach is simplistic. The first is that anti-IL-4 based approach (by complex formation between IL-4 and soluble IL-4 receptors or serum binding proteins) may actually increase the persistence of IL-4 and its effects instead of inhibiting them. Secondly, we have good evidence in mouse model systems that a period of exposure to IL-4 will result in an increased population of gamma 1,epsilon-double positive B-cells allowing an increased serum IgE level to persist for extensive periods of time. These B-cells turn out to be partially independent of IL-4 for their IgE formation. Moreover, these B-cells are partially independent of a cognate interaction with T-cells for their subsequent IgE synthesis. Therefore, we hypothesize that an approach geared solely at inhibiting IL-4 is not sufficient for decreasing persistent IgE levels in allergic patients.